TGF-β1 in tumor microenvironments induces immunosuppression in the tumors and sentinel lymph nodes and promotes tumor progression

Shoko Nakamura, Tomonori Yaguchi, Naoshi Kawamura, Asuka Kobayashi, Toshiharu Sakurai, Hajime Higuchi, Hiromasa Takaishi, Toshifumi Hibi, Yutaka Kawakami

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

In cancer patients, sentinel lymph nodes (SLNs) are crucial in the induction of antitumor T cells. However, in many cases, SLNs and tumors appear to be in immunosuppressive condition through mechanisms yet to be elucidated. In this study, the role of tumor-derived TGF-β1 in the generation of immunosuppressive microenvironments of tumors and SLNs was investigated. Murine colorectal carcinoma CT26 transduced with TGF-β1 cDNA (CT26-TGF-β1) showed enhanced tumor growth compared with mock-transduced CT26 (CT26-Mock) when implanted in syngeneic Balb/c mice, even though CT26-TGF-β1 shows slower growth in vitro. This enhanced growth was not observed when implanted in immunodeficient mice, suggesting that TGF-β1 enhanced tumor growth by suppressing antitumor T-cell responses. Analysis of immune cells in CT26-TGF-β1-implanted mice revealed impairment of dendritic cells (DCs), decrease of CD8 T cells, and increase of MDSCs and Tregs in the tumors. Similarly, the SLNs of these mice showed an increase of MDSCs, Tregs, and PD-L1 DCs, and decrease of T-cell stimulatory activity of DCs accompanied by decreased CD80 expression and TNF-α production. In addition, induction of tumor antigen-specific T cells from SLNs of the CT26-TGF-β1-implanted mice was significantly reduced. These results demonstrate that overproduction of TGF-β1 is critical for the generation of immunosuppressive microenvironments in both tumors and SLNs, which may result in suppression of spontaneous antitumor CD8 T-cell responses. Therefore, TGF-β1 is an attractive target for restoration of immunosuppressive condition in cancer patients.

Original languageEnglish
Pages (from-to)63-72
Number of pages10
JournalJournal of Immunotherapy
Volume37
Issue number2
DOIs
Publication statusPublished - 2014 Feb

Fingerprint

Tumor Microenvironment
Immunosuppression
Immunosuppressive Agents
T-Lymphocytes
Neoplasms
Complementary DNA
Dendritic Cells
Growth
Sentinel Lymph Node
Neoplasm Antigens
Colorectal Neoplasms

Keywords

  • cancer immune evasion
  • immunosuppression
  • sentinel lymph node
  • TGF-β

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology

Cite this

TGF-β1 in tumor microenvironments induces immunosuppression in the tumors and sentinel lymph nodes and promotes tumor progression. / Nakamura, Shoko; Yaguchi, Tomonori; Kawamura, Naoshi; Kobayashi, Asuka; Sakurai, Toshiharu; Higuchi, Hajime; Takaishi, Hiromasa; Hibi, Toshifumi; Kawakami, Yutaka.

In: Journal of Immunotherapy, Vol. 37, No. 2, 02.2014, p. 63-72.

Research output: Contribution to journalArticle

Nakamura, Shoko ; Yaguchi, Tomonori ; Kawamura, Naoshi ; Kobayashi, Asuka ; Sakurai, Toshiharu ; Higuchi, Hajime ; Takaishi, Hiromasa ; Hibi, Toshifumi ; Kawakami, Yutaka. / TGF-β1 in tumor microenvironments induces immunosuppression in the tumors and sentinel lymph nodes and promotes tumor progression. In: Journal of Immunotherapy. 2014 ; Vol. 37, No. 2. pp. 63-72.
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